Histone methyltransferase MLL4 protects against pressure overload-induced heart failure via a THBS4-mediated protection in ER stress.

Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.

Two New Protolimonoids from the Chinese Mangrove Xylocarpus granatum Koenig.

Two new compounds including one apotirucallane protolimonoid, xylogranatriterpin A (1), and one glabretal protolimonoid, xylocarpusin A (2), along with three known related compounds were isolated from the twigs and leaves of the Chinese mangrove Xylocarpus granatum. The apotirucallane xylogranatriterpin A (1) bears an unprecedented 24-ketal carbon connecting ring E with an epoxide ring. The structures of new compounds were elucidated by extensive spectroscopic analysis and by comparison of the spectroscopic data with those reported in the literatures. Plausible biosynthetic pathway to xylogranatriterpin A (1) was also proposed. None of them showed cytotoxic, neuroprotective, or protein tyrosine phosphatase 1B (PTP1B) inhibitory activity.

Marine bis-γ-pyrone polypropionates of onchidione family and their effects on the XBP1 gene expression.

Two additional new members of the onchidione family, 16-epi-onchidione (1) and 4-epi-onchidione (2), co-occurring with six previously reported bis-γ-pyrone polypropionates including onchidione (3), were isolated from the marine pulmonate Onchidium sp. Their structures were determined by extensive spectroscopic analysis and by comparison with 3 and onchidione-related derivatives. The absolute configuration of 1 was established by X-ray diffraction analysis employing graphite monochromated Cu Kα radiation (λ = 0.71073 Å) with small Flack parameter 0.08. In addition, the absolute stereochemistry of previously reported onchidionol (6) was confirmed by the X-ray diffraction analysis. Some of the isolated compounds showed significant activation effects on the splicing of XBP1 mRNA as ER stress modulators to inhibit the growth of tumors.

Four phragmalin orthoesters from the Chinese mangrove Xylocarpus granatum.

Four new 8,9,30-phragmalin orthoesters (1-4), along with six related known compounds, namely xyloccensins O-S (5-9) and V (10), were isolated and characterized from the twigs and leaves of the Chinese mangrove Xylocarpus granatum. The structures of the new compounds were determined on the basis of extensive spectroscopic analysis and by comparison with those of related known compounds in the literature. The absolute configuration of xyloccensin Q (7) was revised as its enantiomer by X-ray diffraction analysis employing graphite monochromated Cu Kα radiation (λ=1.54178 Å) with a Flack parameter of -0.04 and was further secured by a time-dependent density functional theory electronic circular dichroism (TDDFT ECD) calculation. Consequently, the absolute configurations of xyloccensins O (5), P (6), R (8), S (9), and V (10) were all corrected as their corresponding enantiomers, respectively. Xyloccensin S (9) exhibited inhibitory activity against protein tyrosine phosphatase 1B, a potential drug target for the treatment of type II diabetes and obesity, with an IC50 value of 8.72 µg/mL.

Evaluation of time-dependent phenotypes of myocardial ischemia-reperfusion in mice.

BACKGROUND: A mouse model of myocardial ischemia-reperfusion (I/R) is widely used to study myocardial ischemia-reperfusion injury (I/RI). However, few studies focus on the direct comparison of the extent of pathological events resulting from variant durations of ischemia and reperfusion process. METHODS: A mouse model of I/RI was established by ligation and perfusion of the left anterior descending coronary artery (LAD), and the dynamic changes were recorded by electrocardiogram at different stages of I/R. Subsequently, reperfusion duration was used as a variable to directly compare the phenotypes of different myocardial injury degrees induced by 3 h, 6 h and 24 h reperfusion from myocardial infarct size, myocardial apoptosis, myocardial enzyme, and inflammatory cytokine levels. RESULTS: All mice subjected to myocardial I/R surgery showed obvious myocardial infarction, extensive myocardial apoptosis, dynamic changes in serum myocardial enzyme and inflammatory cytokines, at least for the first 24 h of reperfusion. The infarct size and apoptosis rates gradually increased with the extension of reperfusion time. The peaks of serum myocardial enzyme and inflammatory cytokines occurred at 6 h and 3 h of reperfusion, respectively. We also established I/R mice models with 30 and 60 mins of ischemia. After 21 days of remodeling, longer periods of ischemia increased the degree of fibrosis and reduced cardiac function. CONCLUSIONS: In summary, we conclude that reperfusion durations of 3 h, 6 h, and 24 h induces different injury phenotypes in ischemia-reperfusion mouse model. At the same time, the ischemia duration before reperfusion also affects the degree of cardiac remodeling.

Bioactive natural products from Chinese marine flora and fauna.

In recent decades, the pharmaceutical application potential of marine natural products has attracted much interest from both natural product chemists and pharmacologists. Our group has long been engaged in the search for bioactive natural products from Chinese marine flora (such as mangroves and algae) and fauna (including sponges, soft corals, and mollusks), resulting in the isolation and characterization of numerous novel secondary metabolites spanning a wide range of structural classes and various biosynthetic origins. Of particular interest is the fact that many of these compounds show promising biological activities, including cytotoxic, antibacterial, and enzyme inhibitory effects. By describing representative studies, this review presents a comprehensive summary regarding the achievements and progress made by our group in the past decade. Several interesting examples are discussed in detail.

Antibacterial sorbicillin and diketopiperazines from the endogenous fungus Penicillium sp. GD6 associated Chinese mangrove Bruguiera gymnorrhiza.

One new sorbicillin derivative, 2-deoxy-sohirnone C (1), one new diketopiperazine alkaloid, 5S-hydroxynorvaline-S-Ile (2), and two naturally occurring diketopiperazines, 3S-hydroxylcyclo(S-Pro-S-Phe) (3) and cyclo(S-Phe-S-Gln) (4), together with three known compounds were isolated from the Chinese mangrove endophytic fungus Penicillium sp. GD6. Their structures were determined on the basis of extensive spectroscopic analyses and by comparison with literature data. The absolute configuration of 3-hydroxyl moiety in 3 was determined by Mosher's method, while the absolute stereochemistry of 2 and 4 was established by comparison with the CD spectra of natural and synthesized diketopiperazines. Compound 1 showed moderate antibacterial activity against Methicillin-resistant Staphylococcus aureus with a MIC value of 80 µg·mL-1.

Novel and Neuroprotective Tetranortriterpenoids from Chinese Mangrove Xylocarpus granatum Koenig.

Eight new tetranortriterpenoids (1-8) were isolated from the twigs and leaves of the Chinese mangrove plant Xylocarpus granatum, together with four related known ones (9-12). The structures of new compounds were elucidated by detailed spectroscopic analysis. The absolute configuration of 9-epixylogranatin A (1) was determined by time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD) calculations of the solution conformers. Xylogranatumin A (2) represents the first example of the 9, 10-seco limonoid with an unprecedented oxygen-bridged B ring (2,7-dioxabicyclo[2.2.1]-heptane). All the isolates were evaluated for the in vitro neuroprotective activity, both compounds 11 and 12 displayed moderate effects against H2O2-induced neurotoxicity in PC12 cells at the concentration of 10 µM, with an increase in cell viability of 12.0% and 11.6%, respectively.

Penibruguieramine A, a novel pyrrolizidine alkaloid from the endophytic fungus Penicillium sp. GD6 associated with Chinese mangrove Bruguiera gymnorrhiza.

A novel pyrrolizidine alkaloid, penibruguieramine A (1), characterized by an unprecedented 1-alkenyl-2-methyl-8-hydroxymethylpyrrolizidin-3-one skeleton, was isolated from the endophytic fungus Penicillium sp. GD6, associated with the Chinese mangrove Bruguiera gymnorrhiza. The absolute configuration of penibruguieramine A (1) was established by TDDFT ECD calculations of the vacuum and solution conformers, exploiting the transitions of the lactam chromophore. A plausible pathway for its biosynthesis has been proposed.

Apotirucallane protolimonoids from the Chinese mangrove Xylocarpus granatum Koenig.

A series of previously unreported compounds including seven new apotirucallane protolimonoids, xylogranatumines A-G (1-7), were isolated together with three known analogues (8-10) from the twigs and leaves of the Chinese mangrove, Xylocarpus granatum. The structures of these new compounds were elucidated by extensive spectroscopic analysis including 1D and 2D NMR and high-resolution electrospray ionization mass spectrometry (HRESIMS) and by comparison with those of related known compounds in the literature. Xylogranatumine F (6) exhibited cytotoxic activity against A549 tumor cell in vitro.